Intrathecal administration of epinephrine inhibits and reverses analgesic tolerance to morphine in rats

Introduction: Several researches have reported that stress is able to inhibit the development of morphine tolerance via activating of Hypothalamic-Pituitary-Adrenal (HPA) axis. In the present study we tried to examine the effect of epinephrine, the product of adrenal medulla, on the development of morphine tolerance. Methods: Analgesic tolerance was induced by intrathecal (i. t.) injection of morphine 15 mu g/kg, twice a day for 5 days. To study the effect of epinephrine on morphine tolerance, epinephrine (2, 5, 10 or 20 mu g/kg, i. t.) was administrated 20 minutes before morphine injection. Analgesia was assessed using tail flick test. Results: In animals that received combined treatments of morphine and epinephrine in doses 2, 5, 10 or 20 mu g/ kg for 5 days, at 6th day, morphine produced a more potent analgesia comparing with animals that received saline and morphine during days 1-5. Following tolerance induction during first 5 days, co-administration of epinephrine and morphine during days 6 -10 reduced the initial tolerance as it induced potent analgesia on day 11th. Conclusion: Our results showed that i. t. administration of epinephrine is able to inhibit and reverse the analgesic tolerance to morphine. It also suggests the possible role of adrenal medulla and epinephrine in mediating the inhibitory effect of stress and HPA activation of the development of analgesic tolerance to morphine.